1. Field of the Discovery
The present invention relates generally to a method of obtaining three dimensional structures of TorsinA, and more particularly to obtaining three dimensional structures of TorsinA via a protein composition, and applications of the same.
2. Background Information
Early-onset torsion dystonia (DYT1) is a genetic disease affecting an estimated 50,000 patients in the United States alone (Steeves et al., 2012). It is an incurable and severely debilitating neuromuscular disease (Breakefield et al., 2008). A single glutamate deletion at position 302 or 303 (ΔE) of the protein TorsinA is the primary cause for DYT1 (Ozelius et al., 1997).
TorsinA is a member of the ATPases Associated with diverse cellular Activities (AAA+) protein family. TorsinA resides in the endoplasmic reticulum of the cell, including the perinuclear space. The function of the protein is unclear, but it presumably acts in protein or membrane remodeling. It has been shown that TorsinA is activated by lamina-associated protein 1 (LAP1) and by luminal domain-like LAP1 (LULL1) (Sosa et al., 2014).
A glutamate deletion (ΔE) at position 302/303 of TorsinA is the most common cause of early onset primary dystonia, a neuromuscular disease. TorsinAAE weakens the binding of the activators LAP1/LULL1, which likely represents the molecular basis for the disease. If binding to the activator can be restored, for example by a small molecule, this might well represent the drug needed to cure the disease. Conceptually, this is similar to the action of Vertex′ Kalydeco drug for cystic fibrosis patients, which also partially restores the function of a protein. Human TorsinA is an extremely difficult protein to handle in vitro, and can barely be produced recombinantly.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.